Preparation of o-isopropylaminobenzophenones

ABSTRACT

1. A PROCESS FOR PREPARING A COMPOUND OF THE FORMULA:   1-((H3C)2-CH-NH-),2-(R&#39;&#39;-CO-),(R)N-BENZENE   WHEREIN R REPRESENTS HALO, LOWER ALKYL, LOWER ALKOXY, NITRO OR TRIFLUOROMETHYL; N REPRESENTS 0, OR 2; PROVIDED THAT WHEN N IS 2 R IS EITHER LOWER ALKYL OR LOWER ALKOXY; R&#39;&#39; REPRESENTS PHENYL OR SUBSTITUTED PHENYL OF THE FORMULA   Y,Y&#39;&#39;-PHENYL-   Y REPRESENTS HALO, HYDROXY, LOWER ALKYL, LOWER ALKOXY OR TRIFLUOROMETHYL; AND Y&#39;&#39; REPRESENTS HYDROGEN, HALO, HYDROXY, LOWER ALKYL OR LOWER ALKOXY; WHICH CONSISTS ESSENTIALLY OF REACTING A COMPOUND OF THE FORMULA   1-(H2N-),2-(R&#39;&#39;-CO-),(R)N-BENZENE   WHEREIN R, R&#39;&#39; AND N ARE AS DEFINED ABOVE, WITH AT LEAST A 25% STOICHIOMETRIC EXCESS OF AN ISOPROPYL HALIDE SELECTED FROM THE GROUP CONSISTING OF ISOPROPYL BROMIDE OR ISOPROPYL IODIDE, AT AN ELEVATED TEMPERATURE OF AT LEAST ABOUT 60*C. FOR A TIME OF AT LEAST 10 HOURS, AND ISOLATING THE RESULTING REACTION PRODUCT CONSISTING ESSENTIALLY OF AN 0-MONISOPROYLAMINOBENZOPHENONE IN YIELD OF AT LEAST 70% BASED ON THE STARTING O-AMINOBENZOPHENONE.

United States Patent 3,845,128 PREPARATION OF o-ISOPROPYLAMINO-BENZOPHENONES Max Denzer, Lake Parsippany, N.J., and Hans Ott,Pfeflingen, Basel-Land, Switzerland, assignors to Sandoz-Wander, Inc.,Hanover, NJ. No Drawing. Continuation-impart of abandoned applicationSer. No. 679,201, Oct. 30, 1967. This application Aug. 5, 1970, Ser. No.61,453

Int. Cl. C07c 97/10 US. Cl. 260-570 AB 6 Claims ABSTRACT OF THEDISCLOSURE Preparation of o-alkylaminobenzophenones by reaction of anoaminobenzophenone with an alkyl halide, the oalkylaminobenzophenonesbeing intermediates for the preparation of the corresponding2(1H)-quinazolinones.

This application is a continuation-in-part of our prior application Ser.No. 679,201, filed Oct. 30, 1967, now abandoned.

This invention relates to a process for the preparation of ano-substituted aminobenzophenone. In particular, the invention pertainsto a process for preparing an o-isopropylaminobenzophenone asillustrated by the following reaction scheme:

CH3 /CH3 (3H NHZ (CHihCHX NH (R) n )1 C=O C=O 1'1 la wherein Xrepresents bromo or iodo;

R represents halo, preferably having an atomic weight no greater than80, i.e., fluoro, bromo and chloro; lower alkyl, preferably having from1 to 4 carbon atoms, e.g., methyl, ethyl, propyl or butyl; lower alkoxy,preferably containing from 1 to 4 carbon atoms, e.g., methoxy, ethoxy,propoxy or butoxy; nitro; or trifluoromethyl;

n represents 0, 1 or 2; provided that when n is 2 each R is the same andeither lower alkyl or lower alkoxy;

R represents phenyl; or substituted phenyl of the formula Thepreparation of o-alkylaminobenzophenones has heretofore beenaccomplished by first tosylating o-aminobenzophenone, alkylating theresulting tosylated intermediate and then removing the protecting tosylgroup by hydrolysis. While this process is suitable for preparingoal-kylarninobenzophenone wherein the alkyl moiety is a straight chainalkyl, it is not particularly suitable for the preparation of thosecompounds wherein the alkyl moiety 3,845,128 Patented Oct. 29, 1974 ice"is a branched chain and the branching occurs on the carbon atom directlyattached to the ring nitrogen atom in that there is a significantreduction in the yield of the desired product due to steric hinderance.

In accordance with the present invention, there is now provided aprocess whereby an o-isopropylaminobenzophenone is obtained withfacility in one step and in excellent yields. As indicated hereinabove,the process of the present invention involves reacting ano-aminobenzophenone with isopropyl bromide or isopropyl iodide,preferably the latter. Desirably, the reaction is carried out in thepresence of an acid binding agent to take up the hydrogen halideliberated during the reaction. Any of the several acid binding agents ofknown type may be employed including the inorganic bases such as thealkali metal carbonates, e.g., sodium carbonate, potassium carbonate andlithium carbonate, and the organic bases such as the tertiary amines,e.g., triethylamine. The preferred acid binding agents are the alkalimetal carbonates, more preferably sodium carbonate or potassiumcarbonate. The reaction is desirably carried out with a stoichiometricexcess of at least about 25% of the isopropyl halide, preferably a 50%to 500% stoichiometric excess. If desired, the reaction may be carriedout in any suitable inert organic solvent, e.g., dioxane, benzene andtoluene. However, the use of a solvent is not necessary since an excessof the isopropyl halide can be utilized for this purpose. The reactionis most conveniently effected at elevated temperatures. Desirably, thereaction is carried out at a temperature of at least about 60 C.,usually 60 C. to 100 C. Preferably, the reaction is conducted at thereflux temperature of the system. However, the particular temperatureemployed is not particularly critical and somewhat lower or highertemperatures and/ or elevated pressures can be employed. A feature ofthe process of the invention is that it results in the production of areaction product which consists essentially of the desiredo-monoisopropylaminobenzophenone to the substantial exclusion ofdiisopropylated by-products, i.e., the reaction product contains no morethan about 3% of diisopropylated material, and more typically thereaction product contains only a trace or no amounts of diisopropylatedby-product. Accordingly, the process enables the production ofomonoisopropylaminobenzophenones in high yields of the order of at leastabout 70%, and yields of typically to may be readily and efficientlyobtained with the process of the invention. Reaction times may vary overa fairly wide range depending upon known factors such as reactiontemperature and starting materials employed in the reaction. Highconversions of the o-aminobenzophenone starting material of at leastabout 7075% and high yields of at least about 70% of the desiredo-monoisopropylaminobenzophenone may be obtained in as little as 10hours, with higher yields of the order of 8095% of the desired productusually obtained when the reaction is conducted over a period of about20 to hours. The production of the desired o-isopropylaminobenzophenonein high yield and to the substantial exclusion of diisopropylatedby-product by the process of the invention is unexpected and surprising,particularly in view of the fact that such results are obtained despitethe use of substantial excess amounts of the isopropyl halide.

It should be noted that the reaction proceeds independently of theparticular substituents attached to the phenyl rings. Accordingly, whilethe process of the invention is specifically exemplified with respect tocertain substituents attached to either or both of the phenyl rings, itnevertheless can be utilized for the preparation of all of the compoundsincluded within the scope of the invention.

The compounds of formula 11 prepared in accordance with this inventionare useful as intermediates for the preparation of the corresponding1-isopropyl-4-aryl- 2(1H)-quinazolinones in accordance with thefollowing reaction scheme:

wherein R, R and n are as previously defined.

In accordance with the above process, an o-isopropylaminobenzophenone(II) is reacted with ethyl carbamate in the presence of a catalyticamount of a Lewis acid, e.'g., zinc chloride, and at elevatedtemperatures.,Preferably, the reaction is eflf'ected at a temperature offrom about 160 C. to about 200 C. If desired, the reaction may becarried out in the presence of a suitable inert organic solvent.However, the use of a solvent is not necessary since an excess of thecarbamate can be used for this purpose.

Various of the o-aminobenzophenones (I) employed as starting materialsin the process of this invention are known and can be prepared asdescribed in the literature. Such others which may not be specificallydescribed in the literature can be readily prepared from availablematerials in analogous manner.

The quinazolinones (III) obtained from the compounds produced inaccordance with the process of this invention are useful because theypossess pharmacological activity in animals. In particular, suchcompounds are useful as anti-inflammatory agents as indicated by thecarrageenininduced edema test on rats, and the antagonism ofbradykinin-induced broncho-constriction of the guinea pig. For such use,the compounds may be combined with a pharmaceutically acceptablecarrier, and such other conventional adjuvants as may be necessary, andadministered orally in such forms as tablets, capsules, elixirs,suspensions and the like or parenterally in the form of an injectablesolution or suspension. For the above-mentioned use, the dosageadministered will, of course, vary depending upon the compound used andmode of administration. However, in general, satisfactory results areobtained when administered at a daily dosage of from about 2. milligramsto about 20* milligrams per kilogram of body weight, preferably given individed doses 2 to 4 times a day, or in sustained release form. For mostmammals, the administration of from about 150 milligrams to about 600milligrams of the compound per day provides satisfactory results anddosage forms suitable for internal administration comprise from about37.5 milligrams to about 300 milligrams of the compound in admixturewith a solid or liquid pharmaceutical carrier or diluent. Arepresentative formulation is a tablet prepared by conventionaltabletting techniques and containing, by weight, 50 parts ofl-isopropyl-4-phenyl-2(1H) -quinazolinone, 2 parts of tragacanth, 39.5parts of lactose, 5 parts of corn starch, 3 parts of talcum and 0.5parts of magnesium stearate.

The following examples illustrate the preparation of representativecompounds utilizing the process of this invention. However, it is to beunderstood that the examples are for purposes of illustration only andare not intended as in any way limiting the scope of the invention whichis defined in the appended claims.

EXAMPLE 1 o-Isopropylaminobenzophenone A mixture of 20 g. ofo-aminobenzophenone, g. of sodium carbonate and 50 ml. of isopropyliodide is re fluxed with stirring for 5 days. The excess isopropyliodide is then evaporated off in vacuo, and the resulting residueextracted with 200 ml. of benzene. The benzene extract is then filtered,washed twice with 100 ml. (each) of water, dried over anhydrous sodiumsulfate, filtered and evaporated to dryness in vacuo to obtaino-isopropylaminobenzophenone as an oil.

EXAMPLE 2 5-chloro-2-isopropylaminobenzophenone A mixture of 10 g. of5-chloro-2-aminobenzophenone, 5 g. of sodium carbonate and 30- ml. ofisopropyl iodide is refluxed with stirring for 2% days. The excessisopropyl iodide is then evaporated off in v'acuo and the resultingresidue extracted with 200 ml. of benzene. The benzene extract is thenfiltered, Washed twice with 100 ml. (each) of water, dried overanhydrous sodium sulfate, filtered and evaporated to dryness in vacuo toobtain 5-chloro-2-isoproplyaminobenzophenone as an oil.

EXAMPLE 3 2-isopropylamino-4'-methylbenzophenone A mixture of 5 g. of2-amino-4'-methylbenzophenone, 5 g. of sodium carbonate and 20 ml. ofisopropyl iodide is refluxed with stirring for 5 days. The excessisopropyl iodide is then evaporated oif in vacuo and the resultingresidue extracted with 200 ml. of benzene. The benzene extract is thenfiltered, washed twice with 100 ml. (each) of water, dried overanhydrous sodium sulfate, filtered and evaporated to dryness in vacuo toobtain 2-isopropylamino-4-methylbenzophenone as an oil.

EXAMPLE 4 4,5-dimethyl-2-isopropylaminobenzophenone A mixture of 9.5 g.of 2-amino-4,5-dimethylbenzophenone, 5 g. of sodium carbonate and 30 ml.of isopropyl iodide is refluxed with stirring for 20 hours. The excessisopropyl iodide is then evaporated ofl in vacuo and the resultingresidue extracted with 200 ml. of benzene. The benzene extract is thenfiltered, washed twice with 100 ml. (each) of water, dried overanhydrous sodium sulfate, filtered and evaporated to dryness in vacuo toobtain 4,S-dimethyl-Z-isopropylaminobenzophenone as an oil which isfurther purified chromatographically on an aluminum oxide column.

EXAMPLE 5 2-isopropylamino-5-trifluoromethylbenzophenone EXAMPLE 61-isopropyl-4-phenyl-2 lH -quinazolinone A mixture of 21 g. of crudeo-isopropylaminobenzophenone, 40 g. of urethane and 1.5 g. of zincchloride is heated for 4 hours at l-200 C. (oil bath). The resultingmixture is cooled to room temperature and then there is added thereto200 ml. of methylene chloride. The resulting mixture is filtered and thefiltrate extracted twice with ml. (each) of water. The organic phase isdried over anhydrous sodium sulfate and evaporated in vacuo. The residueis crystallised from ethyl acetate to obtainl-isopropyl-4-phenyl-2(lH)-quinazolinone, m.p. C.

What is claimed is: 1. A process for preparing a compound of theformula:

wherein R represents halo, lower alkyl, lower alkoxy, nitro ortrifluoromethyl; n represents 0, l or 2; provided that when n is 2 R iseither lower alkyl or lower alkoxy; R represents phenyl or substitutedphenyl of the formula Y represents halo, hydroxy, lower alkyl, loweralkoxy or trifiuoromethyl; and Y represents hydrogen, halo, hydroxy,lower alkyl or lower alkoxy; which consists essentially of reacting acompound of the formula wherein R, R and n are as defined above, with atleast a 25% stoichiometric excess of an isopropyl halide selected fromthe group consisting of isopropyl bromide or isopropyl iodide, at anelevated temperature of at least about C. for a time of at least 10hours, and isolating the resulting reaction product consistingessentially of an o-monoisopropylaminobenzophenone in yield of at leastbased on the starting o-aminobenzophenone.

2. A process of claim 1 wherein the reaction is carried out in thepresence of an acid binding agent.

3. A process of claim 1 wherein the reaction is carried out at atemperature in the range of from about 60 to and in the presence of analkali metal carbonate as acid binding agent.

4. A process of claim 3 wherein the temperature is the refluxtemperature of the system.

5. A process of claim 2 wherein isopropyl iodide is employed.

6. A process of claim 5 wherein isopropyl iodide is employed.

References Cited UNITED STATES PATENTS 3,005,026 10/1961 Gordon 2605773,121,077 2/1964 Keller et al. 260-239.3

ROBERT V. HINES, Primary Examiner US. Cl. X.R.

1. A PROCESS FOR PREPARING A COMPOUND OF THE FORMULA: